Conventionally, medicaments having a renoprotective effect (suppression of proteinuria, suppression of renal hypofunction) have been used for the treatment of diabetic nephropathy. Of such medicaments, only the antihypertensive agents of angiotensin II receptor blocker (ARB) and angiotensin converting enzyme inhibitor (ACEI) showed efficacy in large scale clinical trials (New England Journal of Medicine (GB), vol. 329, pp. 1456-1462 (1993)). Since ARB and ACEI have a hypotensive action, their usefulness for patients without hypertension has not been clarified, and suppression of progress of diabetic nephropathy only with the current medicaments is considered to be difficult. Therefore, the development of a potent renoprotective agent free of hypotensive action has been strongly demanded.
In the meantime, AGEs have been known to result from modification of protein by a reactive carbonyl compound produced due to hyperglycemia and oxidative stress in the lesion of diabetic nephropathy. Recently, it has been proved that several kinds of medicaments of ARB and ACEI inhibit formation of AGEs, and the renoprotective effect of ARB and ACEI is exerted independent of the hypotensive action. In addition, it has also been clarified that renal disorder depends on the-amount of AGEs contained in the kidney tissue rather than the blood pressure, and that the administration of ARB decreases the amount of AGEs as well as the renoprotective effect.
From the foregoing, since the amount of AGEs contained in kidney tissue could be a significant index of disorder in diabetic nephropathy, the development of a medicament that specifically inhibits AGEs formation is considered to lead to the production of a powerful renoprotective agent free of a hypotensive action.
WO02/083127 discloses a compound having a partially common structure with the phenylene derivative of the present invention, and showing an AGEs formation inhibitory action. However, the compound is different from the compound of the present invention in that a biphenyltetrazole skeleton is essential.
In addition, JP-A-10-310524 discloses a compound having a partially common structure with the phenylene derivative of the present invention, and showing a nephritis inhibitory action. However, the compound is different from the compound of the present invention in that a biphenyltetrazole skeleton is essential and it has an angiotensin II receptor antagonistic action.